The present invention relates to a novel purine derivative dihydrate with a phosphodiesterase IV inhibitory effect, to drugs containing the dihydrate as an active ingredient and to a method of using the drugs. The invention further relates to a compound useful as an intermediate in the production of the purine derivative dihydrate.
Cyclic AMP (cAMP) is an important second messenger which is involved in relaxation of respiratory tract smooth muscles and control of inflammatory cells, and the messenger is decomposed by phosphodiesterase (hereinafter abbreviated as xe2x80x9cPDExe2x80x9din the specification) to be converted into inactive 5xe2x80x2-AMP. Therefore, it is believed that suppression of the decomposition of cAMP by PDE may increase the concentration of cAMP, thereby bronchodilatation and anti-inflammatory action can be achieved. For this reason, PDE inhibitors having inhibitory action against the decomposition of cAMP have been focused as medicaments for the treatment of asthma, chronic obstructive pulmonary disease (hereinafter abbreviated as xe2x80x9cCOPDxe2x80x9d in the specification) and/or other inflammatory diseases. In addition, five PDE isozymes (PDE I, II, III, IV and V) have recently been isolated, and their specific tissue distributions have been revealed (Adv. Second Messenger Phosphoprotein Res., 22, 1 (1988): Trends Pharm., Sci., 11,150 (1990)).
Among inhibitors for these isozymes, in particular, inhibitors specific for PDE IV have been suggested to be possibly useful for the treatment of asthma, COPD and/or other inflammatory diseases (Thorax 46, 512 (1991) etc.). Herein, chronic articular rheumatism, atopic dermatitis, psoriasis, etc., are listed as concrete examples of the inflammatory disease. As a compound having specific inhibitory activity against PDE IV, for example, the compound disclosed in Japanese Patent Unexamined Publication (Kokai) No. 50-157360/1975 (Rolipram) has been known. 
Although various compounds have been known as PDE IV inhibitors (for example, compounds disclosed in Japanese Patent Unexamined Publication (Kokai) No. 4-253945/1992, International Patent Publication in Japanese (Kohyo) Nos. 6-504782/1994, 7-504442/1995, 8-501318/1996and9-500376/1997 and so forth), they have not been used clinically so far, and development of novel compounds having PDE IV inhibitory activity has been desired.
As a result of diligent research directed toward providing a novel compound which has a specific inhibitory effect against PDE IV and is useful for asthma, COPD and/or other inflammatory diseases, the present inventors have found that specific purine derivatives have an excellent inhibitory effect against PDE IV (WO99/24432). Upon continued investigation, the present inventors discovered a specific purine derivative dihydrate with excellent stability as well as an intermediate useful for its production, and the present invention has thus been completed.
In other words, the present invention provides a dihydrate of 4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurin]-2-yl-3-oxypropyl]pyridine N-oxide and a process for its production.
According to another aspect, the invention provides drugs containing the dihydrate as an active ingredient thereof. Such drugs are preferably provided as pharmaceutical compositions containing the dihydrate and formulating additives, and may be used, for example, as preventives and/or remedies for asthma, COPD and/or other inflammatory diseases. According to yet another aspect, the invention provides the use of the aforementioned dihydrate for production of the aforementioned drugs; therapeutic treatment, that is, a remedy and/or preventive for asthma, COPD and/or other inflammatory diseases which comprises a step of administering an effective dose of the dihydrate to a mammalian animal including human; a PDE IV inhibitor containing the dihydrate; and a process for producing the dihydrate by treating anhydride crystals of 4-[[9-[(3-cyclopentyloxy-4-methoxy) benzyl]-6,8-dimethyipurin]-2-yl-3-oxypropyl] pyridine N-oxide under anhydrous conditions.
According to still another aspect, the invention provides a compound represented by the following general formula (I) 
where X is a halogen atom or a group represented by xe2x80x94Sxe2x80x94(CH2)nxe2x80x94A, xe2x80x94SOxe2x80x94(CH2)mxe2x80x94B, xe2x80x94SO2xe2x80x94(CH2)mxe2x80x94B, xe2x80x94OSO2xe2x80x94(CH2)mxe2x80x94B, xe2x80x94OCOxe2x80x94(CH2)mxe2x80x94B or xe2x80x94OPO(OR)xe2x80x94(CH2)mxe2x80x94B (wherein n represents an integer of 0-4, A represents an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic residue, m represents an integer of 0-4, B represents an optionally substituted alkyl group, an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic residue, and R represents an optionally substituted alkyl group), which is useful as an intermediate in the production of 4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurin]-2-yl-3-oxypropyl]pyridine N-oxide.
The invention further provides a compound represented by the following general formula (II): 
where X is as defined above. This compound is also useful as an intermediate in the production of 4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurin]-2-yl-3-oxypropyl]pyridine N-oxide.
The dihydrate of the invention can be produced by treatment under hydrous conditions of anhydride crystals obtained by the process described in Example 5 of WO99/24432, for example. The hydrous conditions are not particularly restricted, and as an example, the production may be carried out by a process of dissolving the anhydride crystals in a hydrous organic solvent (such as hydrous isopropyl alcohol, for example) with warming and then cooling to room temperature for crystallization; a process of allowing the anhydride to stand for several weeks at room temperature under conditions with a relative humidity of 75% or greater; or a process of adding water to the anhydride and heating with warming (for example, about 12 hours at 70xc2x0 C.) and then cooling to room temperature. The dihydrate production process of the invention is of course not limited to treatment under these hydrous conditions.
The dihydrate of the invention has a specific inhibitory effect against PDE IV, and is useful as an active ingredient in drugs for asthma, COPD and/or other inflammatory diseases. In particular, the dihydrate of the invention is stable and has excellent physicochemical properties as an active ingredient for drugs. When the dihydrate of the invention is used as an active ingredient in a drug, the dihydrate itself may be administered directly or as a pharmaceutical composition prepared using pharmacologically acceptable formulating additives. The composition and form of the pharmaceutical composition is determined based on the route of administration, the administration plan, etc. For example, it may be prepared in the form of granules, powders, tablets, hard capsules, soft capsules, syrups, emulsions, suspensions, solutions or the like for oral administration or in the form of an injection for intravenous administration, intramuscular administration or subcutaneous administration. It may also be in the form of powders for injection and prepared at the time of use. Alternatively, it may be a composition for parenteral administration, such as a transdermal agent or transmucosal agent.
For the manufacturer of pharmaceutical compositions suitable for oral, enteral, parenteral, or topical administration, organic or inorganic pharmaceutical additives can be used. These additives may be a solid or liquid, and examples include carriers and diluents for pharmaceutical formulations and the like. As excipients used for the manufacture of solid pharmaceutical compositions, for example, lactose, sucrose, starch, talc, cellulose, dextrin and the like can be used. For the manufacturer of liquid pharmaceutical compositions for oral administration such as emulsions, syrups, suspensions and solutions, commonly used inactive diluents, for example, water, vegetable oils and the like can be used. The pharmaceutical compositions may contain, for example, wetting agents, suspension aids, sweeteners, aromatics, colorants, preservatives and the like as auxiliaries, as well as inactive diluents. A liquid preparation may be prepared and filled in capsules made of a material that can be disintegrated in body such as gelatin. As solvents or suspending agents used for the manufacture pharmaceutical compositions for parenteral administration such as injections, examples include water, propylene glycol, polyethylene glycol, benzyl alcohol, ethyl oleate, lecitin and the like. Method for preparing the pharmaceutical compositions are not particularly limited, and any methods for preparing formulations available in the art can be utilized.
The drugs of the present invention may be used as remedies and/or preventives for asthma, COPD and/or other inflammatory diseases. The dose of the drugs according to the present invention will generally be 0.01-1000 mg and preferably 0.01-100 mg (weight of active ingredient) per day for adults when used for oral administration. The dose is, of course, more preferably adjusted depending on the conditions such as the age, condition and symptoms of the patient or the presence of any simultaneously administered drugs. The above-mentioned daily dose may be administered once a day, spread over two or three administrations per day at appropriate intervals, or intermittently over a period of several days. For use as an injection of drip infusion, a continuous or intermittent dose of 0.001-100 mg (weight of active ingredient) per day for adults is preferred.
The compounds represented by formulas (I) and (II) of the present invention are useful as intermediates in the production of 4-[[9-[(3-cyclopentyloxy-4- methoxy)benzyl]-6,8-dimethylpurin]-2-yl-3-oxypropyl]pyridine N-oxide. Although only one tautomeric form is shown in general formula (I) above, those skilled in the art are well aware of the existence of other tautomeric forms, and all such tautomeric forms are of course included within the scope of the present invention. The compounds represented by formulas (I) and (II) will sometimes exist as salts, or sometimes as hydrates or solvates, and all such substances are also included within the scope of the invention.
In general formulas (I) and (II), X is a halogen atom or a group represented by xe2x80x94Sxe2x80x94(CH2)nxe2x80x94A, xe2x80x94SOxe2x80x94(CH2)mxe2x80x94B, xe2x80x94SO2xe2x80x94(CH2)mxe2x80x94B, xe2x80x94OSO2xe2x80x94(CH2)mxe2x80x94B, xe2x80x94OCOxe2x80x94(CH2)mxe2x80x94B or xe2x80x94OPO(OR)xe2x80x94(CH2)mxe2x80x94B. In these formulas, n represents an integer of 0-4, A represents an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic residue, m represents an integer of 0-4, B represents an optionally substituted alkyl group, an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic residue, and R represents an optionally substituted alkyl group.
The term xe2x80x9chalogen atomxe2x80x9d as used throughout the present specification refers to a fluorine atom, chlorine atom, bromine atom or iodine atom. As alkyl groups there may be used, for example, C1-C7 and preferably C1-C4 linear or branched alkyl groups, and more specifically there may be mentioned methyl, ethyl, n-propyl, isopropyl, n-butyl, isobutyl, sec-butyl, t-butyl, n-pentyl, 1,2-dimethylpropyl, 1,1-dimethylpropyl, n-hexyl, 1-methylpentyl, 2-methylpentyl, 3-methylpentyl, 4-methylpentyl, 1,1-dimethylbutyl, 2,2-dimethylbutyl, 3,3-dimethylbutyl, 1,2-dimethylbutyl, 1,3-dimethylbutyl, 1,2,2-trimethyipropyl, heptyl, 5-methylhexyl, 2,2-dimethylpentyl, 3,3-dimethylpentyl, 4,4-dimethylpentyl, 1,2-dimethylpentyl, 1,3-dimethylpentyl, 1,4-dimethylpentyl, 1,2,3-trimethylbutyl, 1,1,2-trimethylbutyl, 1,1,3-trimethylbutyl and the like. As preferred groups there may be mentioned methyl, ethyl and propyl.
There are no particular restrictions on the type of aromatic hydrocarbon group, but phenyl and naphthyl may be preferably mentioned, with phenyl being most preferred. There are also no particular restrictions on the type of heterocyclic residue, and for example, a heterocyclic residue having 1 to 4 hetero atoms selected from oxygen atom, sulfur atom and nitrogen atom and having 5 to 10 ring-constituting atoms may be used, such as thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, triazolyl group, tetrazolyl group, oxazolyl group, isooxazolyl group, thiazolyl group, isothiazolyl group, pyrrolidinyl group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazynyl group, benzimidazolyl group, indolyl group, quinolyl group, naphthylidinyl group, quinazolinyl group and the like, preferably thienyl group, furyl group, pyrrolyl group, imidazolyl group, pyrazolyl group, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazinyl group, benzimidazolyl group and the like, more preferably a 6-membered heterocyclic residue having one or two nitrogen atoms as the hetero atom(s), for example, pyridyl group, pyridazinyl group, pyrazinyl group, pyrimidinyl group, triazinyl group, piperidyl group, piperidino group, morpholinyl group, morpholino group, piperazinyl group and the like.
There are no particular restrictions on the number of substituents, positions of substituents or types of substituents introduced into the aromatic hydrocarbon group, heterocyclic residue and alkyl group, but they are preferably alkyl groups or halogen atoms. It is preferred for m to be 0. X is preferably a halogen atom or xe2x80x94Sxe2x80x94(CH2)nxe2x80x94A, xe2x80x94SO2xe2x80x94(CH2)mxe2x80x94B, xe2x80x94OSO2xe2x80x94(CH2)mxe2x80x94B or xe2x80x94OCOxe2x80x94(CH2)mxe2x80x94B, and more preferably a halogen atom or a methanesulfonyl, para-toluenesulfonyl, benzenesulfonyl, para-toluenesulfoxy, methanesulfoxy, phenylthio or trifluoroacetoxy group. Particularly preferred are halogen atoms, with chlorine atoms being most preferred.
The compound of formula (I) maybe converted to a compound of formula (II) by reaction with compound (VI) according to the process outlined by the following scheme, and the compound of formula (II) may then be condensed with 3-(4-pyridine)-propanol and the resulting 4-[[9-[(3-cyclopentyloxy-4-methoxy)benzyl]-6,8-dimethylpurin]-2-yl-3 -oxypropyl]pyridine oxidized for conversion to its N-oxide and subsequently subjected to treatment under the hydrous conditions described above to produce the dihydrate of the present invention. 
[In the above scheme, X has the definition given above, Y represents a halogen atom or a group represented by xe2x80x94OSO2xe2x80x94(CH2)mxe2x80x94B, xe2x80x94OCOxe2x80x94(CH2)mxe2x80x94B or xe2x80x94OPO(OR)xe2x80x94(CH2)mxe2x80x94B (wherein m represents an integer of 0-4, B represents an optionally substituted alkyl group, an optionally substituted aromatic hydrocarbon group or an optionally substituted heterocyclic residue, and R represents an optionally substituted alkyl group), with two tautomeric forms being indicated for the compound represented by formula (I).]
Compound (I) is obtained by reacting compound (VII) with from one equivalent to a solvent amount of an orthoacetic acid ester in acetic anhydride, acetic acid or a mixture thereof. If necessary, a solvent such as N-methylpyrrolidone, dimethylformamide, dimethylacetamide or dimethylimidazolidinone may be used, and the reaction may be conducted with addition of 0.01-5 equivalents of an acid such as para-toluenesulfonic acid, methanesulfonic acid, trifluoromethanesulfonic acid, hydrochloric acid, sulfuric acid or the like. The reaction is normally carried out in a nitrogen or argon stream at a temperature in the range of xe2x88x9220 to 150xc2x0 C.
Compound (I) and compound (VI) may be condensed to produce compound (II). The condensation is accomplished by reacting compound (I) with 0.5-5 equivalents of compound (VI) in an appropriate solvent such as dimethylsulfoxide, N,N-dimethylformamide, tetrahydrofuran, methylene chloride or water or a mixed solvent comprising a combination of these solvents. The reaction may be carried out in the presence of 1-5 equivalents of an organic base such as triethylamine, pyridine or N,N-diethylaniline or an inorganic base such as sodium carbonate, potassium carbonate or sodium hydroxide, and if necessary it may be carried out with addition of an additive such as potassium iodide, sodium iodide or tetrabutylammonium iodide. The reaction is normally carried out in a nitrogen or argon stream at a temperature in the range of xe2x88x9220 to 150xc2x0 C.
The condensation of compound (II) and 3-(4-pyridine)-propanol may be accomplished by adding compound (II) and 3-(4-pyridine)-propanol to an appropriate solvent such as N,N-dimethylformamide or tetrahydrofuran or a mixed solvent comprising a combination of these solvents, and then adding 1-5 equivalents of an organic base such as triethylamine, pyridine or N,N-diethylaniline or an inorganic base such as sodium carbonate or sodium hydroxide. The reaction is normally carried out in a nitrogen or argon stream at a temperature in the range of xe2x88x9220 to 150xc2x0 C. Next, compound (III) may be treated with an appropriate oxidizing agent such as meta-perbenzoic acid, magnesium monoperoxyphthalate, oxone, hydrogen peroxide or peracetic acid to obtain the corresponding N-oxide (IV). After subjecting the obtained N-oxide (IV) to crystallization from the hydrous solvent, suspension washing in the hydrous solvent or exposure to high humidity conditions, it may be dried at low temperature to produce the dihydrate of the invention.
A compound represented by formula (II) wherein X is a halogen atom may be produced according to the following scheme. 
The reaction whereby compound (VIII) and compound (IX) are condensed to obtain compound (X) maybe carried out by adding compound (VIII) and compound (IX) in an appropriate solvent such as N,N-dimethylformamide, tetrahydrofuran, methylene chloride or water or a mixed solvent comprising a combination of these solvents, and then adding and reacting 1-5 equivalents of an organic base such as triethylamine, pyridine or N,N-diethylaniline or an inorganic base such as sodium carbonate or sodium hydroxide. The reaction is normally carried out in a nitrogen or argon stream at a temperature in the range of xe2x88x9220 to 150xc2x0 C.
The reaction whereby compound (X) is reduced to obtain compound (XI) may be carried out by dissolving compound (X) in a solvent such as methanol, ethanol or tetrahydrofuran or a mixed solvent comprising a combination of these solvents, and then adding 10-100 wt % of a catalyst such as Raney nickel, palladium carbon, palladium carbon hydroxide or platinum and carrying out the reaction from room temperature to 60xc2x0 C. under a hydrogen stream or pressure. Next, compound (XI) may be reacted with 1-5equivalents of a reactant such as ortho-triethyl acetate without a solvent or in the presence of 1-5 equivalents of an organic acid such as acetic acid, trifluoroacetic acid or tosylic acid or an inorganic acid such as hydrochloric acid, to obtain compound (II). This reaction is normally carried out in a range from room temperature to 250xc2x0 C.
The processes for production of compounds according to the present invention represented by formulas (I) and (II) are not restricted to the production processes described above. The production processes for the compounds in the schemes outlined above are explained concretely and in detail in the examples of the present specification. Thus, a person skilled in the art can, by referring to the general explanation given above and the concrete explanation in the examples, produce any of the compounds included by formulas (I) and (II).